Injectable calcium phosphate cement

ABSTRACT

A calcium phosphate composition comprising at least one calcium phosphate mineral, at least one reaction retarding agent, at least one biding agent, and at least one sodium phosphate compound.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.11/102,254, filed on Apr. 8, 2005, the disclosure of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

The field of this invention pertains to calcium phosphate minerals forbone cement or bone filler applications and in the preparation of suchcement. More specifically, this invention relates to a calcium phosphatebone cement comprising a mixture of tetra-calcium phosphate anddi-calcium phosphate in an aqueous solution, in which the mixture thensets to form a bone cement with a substantial portion of the cementbeing hydroxyapatite.

Hydroxyapatite is the major natural building block of bone and teeth. Ithas been found that bone cements, which are formed by combining calciumand phosphate precursors in an aqueous solution, which initially forms apaste but then hardens into a hydroxyapatite bone cement, are useful infixing fractures and bone defects. Hydroxyapatite has a calcium tophosphorous ratio of approximately 1.67 which is generally the same asthe calcium phosphate ratio in natural bone structures.

These pastes may be placed in situ prior to setting in situations wherebone has been broken, destroyed, degraded, become too brittle or hasbeen the subject of other deteriorating effects. Numerous calciumphosphate bone cements have been proposed such as those taught by Brownand Chow in U.S. Reissue Pat. 33,161 and 33,221, Chow and Takagi in U.S.Pat. No. 5,522,893, and by Constantz in U.S. Pat. Nos. 4,880,610 and5,047,031.

It has been well known since the initial use of calcium phosphatecements that the addition of sodium phosphate solutions, potassiumphosphate solutions or sodium carbonate solutions to the aqueous settingsolution of the calcium phosphate precursors can speed setting times.This is documented in the Chow et al., April, 1991 IADR Abstract No.:2410 and AADR, 1992 Abstract No.: 666 and was known to those skilled inthe art prior to these publications.

Typically, the powder components, which may be a combination oftetra-calcium phosphate and di-calcium phosphate is supplied in asterile form in a blister pack or a bottle, e.g., with contents of 2 to50 g. The liquid, e.g. a molar sodium phosphate solution, distilledwater or sodium chloride solution is usually present in a sterile, glasscontainer, usually a disposable syringe, having a volume of 10 cc. Thepowder and liquid components are usually mixed in a vessel, andprocessed from this vessel, e.g., by means of a syringe or the like.

It is important that these components of bone cements have long-termstability during storage as these components may be stored for weeks ormonths before usage when the powder component is mixed with the aqueouscomponent to form a settable material. But, the long-term stability ofthese components have not been extensively studied because it has beenassumed by those skilled in the art that they stay stable with little orno change in properties.

However, unlike the industry's general assumption, according to UweGbureck et al. in Factors Influencing Calcium Phosphate CementShelf-life, Biomaterials, (Elsevier Ltd. 2004), it has been found thatsome prior art powder mixtures of calcium phosphate lose their abilityto set after only 7 days of storage, despite being stored in sealedcontainers. The deterioration of the prior art powder mixtures wassubsequently found to be related to their conversion to monetite in adry state during aging.

Thus, there is a need to develop a rapid setting bone cement whichovercomes the destabilization problems of the prior art.

Furthermore, there is also a need to develop an injectable and rapidsetting bone cement which can be used in a minimally invasive manner.Minimally invasive surgery is often performed through natural bodyopenings or small “keyhole” incisions, sometimes no more than aquarter-inch in length. When working through such a small opening, it isoften desired or required to use a bone cement which can be injected bymeans of a syringe, for example, into the fractured area.

The commercially available injectable cements currently available in themarket, such as Synthes Norian SRS®, Synthes Norian CRS® and WrightMedical MIG X3®, are formulated so that they are readily injectable.However, they have longer setting times, forcing the surgeon to wait asthe cements set, prolonging the surgery time.

Some other commercially available bone cement products, such as SynthesFast Set Putty®, Lorenz Mimix® are rapid setting, but are not readilyinjectable through a syringe or a needle, rendering the product uselessfor minimally invasive applications.

Therefore, there is also a continued need to develop a rapid settingbone cement with long-term stability, and also is readily injectable,providing a surgeon with optimal working time and a decreased overallset-time during a minimally invasive surgery.

The invention that is described herein fulfills all of the shortcomingsof the currently available commercial products described above.

SUMMARY OF THE INVENTION

It is one aspect of the present invention to provide a rapid settinginjectable calcium phosphate bone cement, preferably with long termshelf-life.

It is also an aspect of the present invention to provide a calciumphosphate bone cement that provides an optimal combination ofinjectability and rapid-setting to meet a surgeon's needs. For example,in some embodiments, the cement of the present invention can be easilymolded in vivo (intraoperatively).

It is further an aspect of the present invention to provide a fullyinjectable bone cement product without the liquid and powder separationwhen mixed.

It is another aspect of the present invention to provide a calciumphosphate bone cement with significantly improved mechanical strengthproperties. For example, soon after the bone cement minerals of thepresent invention are mixed and applied to the defect area, one candrill and put screws into the cement without cracking, which is a commonchallenge with the commercially available products today.

Furthermore, it is an aspect of the invention to provide a method formaking a calcium phosphate bone cement described above and supplying thesame as a kit. For example, in one aspect of the invention, a kit forforming a calcium phosphate bone cement comprises: (a) a first containercomprising a powder mixture of stabilized di-calcium phosphate dihydratecontaining from about 10 ppm to about 60 ppm of magnesium, a secondcalcium phosphate mineral, and at least one reaction retarding agent,and (b) a second container comprising a solvent comprising at least onebinding agent, and at least one sodium phosphate compound.

In one aspect of the invention, a calcium phosphate cement comprises (1)at least one source of calcium phosphate, (2) at least one reactionretarding agent, (3) at least one binding agent, and (4) at least onesodium phosphate compound. It will be appreciated that when thecomponents are mixed and/or set, it may or may not be possible toidentify or distinguish these individual components. Thus, references to“cement” herein include a cement which results from the mixture and/orreaction of these components.

In another aspect of the invention, a calcium phosphate bone cementcomprises the product of a mixture of a powder component and a liquidcomponent, wherein at least one source of calcium phosphate is a partthe powder component, and at least one reaction retarding agent, atleast one binding agent, and at least one sodium phosphate compound area part of either the powder component or the liquid component.

In yet another aspect of the invention, an injectable calcium phosphatecement comprises a powder component comprising (1) a di-calciumphosphate mineral containing from about 10 ppm to about 60 ppm of astabilizing agent, (2) a tetra-calcium phoshpate mineral, (3) and areaction retarding agent; and a liquid component comprising (1) at leastone binding agent, (2) at least one sodium phosphate, and (3) solvent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a characteristic X-ray powder diffraction pattern of DCPDcontaining 40 ppm of magnesium before the accelerated aging test.

FIG. 2 is a characteristic X-ray powder diffraction pattern of DCPDcontaining 40 ppm of magnesium after the accelerated aging test (i.e.,after storage at 50° C. for 77 days).

FIG. 3 is a characteristic X-ray powder diffraction pattern of DCPDcontaining 60 ppm of magnesium before the accelerated aging test.

FIG. 4 is a characteristic X-ray powder diffraction pattern of DCPDcontaining 60 ppm of magnesium after the accelerated aging test (i.e.,after storage at 50° C. for 90 days).

DETAILED DESCRIPTION

Throughout the entire specification, including the claims, the word“comprise” and variations of the word, such as “comprising” and“comprises,” as well as “have,” having,” “includes,” “include,” and“including,” and variations thereof, means that the named steps,elements or materials to which it refers are essential, but other steps,elements, or materials may be added and still form a construct with thescope of the claim or disclosure. When recited in describing theinvention and in a claim, it means that the invention and what isclaimed is considered to what follows and potentially more. These terms,particularly when applied to claims, are inclusive or open-ended and donot exclude additional, unrecited elements or methods steps. The term“cement” herein is used interchangeably with paste, slurry, putty,cement formulation and cement composition. The term “between” as used inconnection with a range includes the endpoints unless the contextsuggests otherwise. The term “long term shelf-life” herein means thatthe calcium phosphate mineral(s) will set when mixed with a solvent toform a cement after the powder has been stored in a sealed containereither with or without the other powder components such as reactionretarding agent for a predetermined period of time, preferably for atleast 1.5 months, more preferably 3 months, and most preferably for atleast 6 months or more according to the accelerated aging test describedin details below in Example 9. The term “injectable” as used inaccordance with the present invention herein means that when the calciumphosphate mineral(s) are mixed with a solvent to form a cement paste andthe paste is transferred to a syringe fitted with a 10 gauge cannula,the injection force measured after 4 minutes and 30 seconds from theinitial blending of the mixture at the ambient temperature of between18° C. to 22° C. as set out in Example 12 below, does not exceed 200 N,and more preferably 150 N. The term “rapid setting” as used inaccordance with the present invention herein means that the calciumphosphate mineral(s) will set when mixed with a solvent to form a cementin about 10 minutes, preferably in about 9 minutes, most preferably inabout 8 minutes, when applied to a defect area, wherein the defecttemperature is about 32° C. The term “set” as used in accordance withthe present invention herein means that the penetration force measuredaccording to the wet field penetration resistance test described indetails below in Example 10 is greater than 3500 pst (24.1 MPa).

Reaction Retarding Agent

The reaction retarding agent in accordance with the present inventioncan be any material useful for retarding the formation of hydroxyapatitewhen calcium phosphate minerals are mixed with a solvent to formhydroxyapatite. If the calcium phosphate minerals set too fast, then itresults in inhomogeneous porous cement matrix, which results in lowcompressive strength. Therefore, a reaction retarding agent is used toslow the rapid dissolution of calcium phosphate minerals during cementmixing and injection.

The reaction retarding agent of the present invention may be supplied toan end user as a powder component or dissolved in a liquid componentwith a solvent. However, in a preferred embodiment, the reactionretarding agent is a powder component.

Examples of a reaction retarding agent which can be used in the presentinvention, without limitation, are trisodium citrate, tripotassiumcitrate, sodium pyrophosphate, EDTA (ethylene diamine tetra acetic acidsodium salt), citric acid, and/or a mixture thereof. The preferredreaction retarding agent is trisodium citrate.

Furthermore, the particle size and/or amount of the reaction retardingagent can be adjusted to modify the rate of the rapid dissolution ofcalcium phosphate minerals during cement mixing and injection. Forexample, the amount and/or particle size of the reaction retarding agentcan be varied so that the bone cement composition is formulated to bedelivered to a fractured area in a long delivery system before it sets.

The particle size of the reaction retarding agent (as well as all otherpowder components) was measured using Beckman Coulter's LS 13320 Seriesparticle size analyzer. A sample for analysis was prepared by adding0.03 gram of powder and 2.5 mL of a carrier medium (in this case,ethanol was used) to a beaker. The slurry was mixed aggressively for 15seconds and then was transferred to a small volume module of the Coultercounter. Prior to the analysis of the sample, a background count wasachieved by first, cleaning the small volume module two times withethanol and then filling the cell with ethanol. The stirrer speed wasturned on to 50% and the measurement of the background was taken. Ifnecessary, the cell can be further cleaned using ethanol.

For sample analysis, the slurry of a reaction retarding agent andethanol mixture was added to the cell until an obscuration value ofroughly 10% was obtained. This sampling procedure was performed with thecell stirring set at 50% to avoid settling of the suspension duringsampling.

Volume distributions were then obtained. Upon measurement completion,the cell was emptied and cleaned and refilled with the slurry ofreaction retarding agent and ethanol mixture, and the sample procedurerepeated for a total of three times.

It is noted that the particle size values mentioned herein refer toVolume Mean Diameter values. Particle size distribution can be measuredby Becton Coulter's LS 13 3220 series particle size analyzer as known tothose skilled in the art and as further disclosed and discussed above.

In accordance with the present invention, the particle size of thereaction retarding agent is between about 1 μm to about 1000 μm,preferably between about 170 μm to about 220 μm. This means that atleast about 25%, preferably about 50%, more preferably about 75% of thereaction retarding agent, by weight, falls within these ranges based onsieving.

In accordance with the present invention the reaction retarding agentcan be provided as a powder component, or dissolved in a solvent andprovided as a liquid component.

With respect to the amount of the reaction retarding agent, the reactionretarding agent may be present in an amount of between about 3% andabout 20%, more preferably between about 5% and about 10% based on thetotal weight of the formulation.

In a preferred embodiment of the present invention, the reactionretarding agent of the present invention is supplied to an end user as apart of the powder component, wherein the reaction retarding agent maybe present in an amount of between about 3% and about 15%, morepreferably between about 5% and about 12.5% based on the total weight ofthe powder component.

Binding Agent

The binding agent of the present invention is used to impart cohesivequalities to the powder material and to improve the free-flowingqualities. The binding agent also aids the mixed cement to flow throughthe syringe and/or cannula easily. The binding agent binds thecomponents together, providing a fully injectable bone cement productwithout the liquid and powder separation, which is a common challengewith the commercially available products today.

The binding agent of the present invention may be supplied to an enduser as a powder component or dissolved in a liquid component with asolvent. However, in a preferred embodiment, the binding agent isdissolved in a solvent and provides as a liquid component.

It is preferred that the binding agent is provided as a part of theliquid component since some of the binding agents may be cleaved orcross-linked when gamma irradiation is used for sterilization of thepowder component of the final product. In addition, if the binding agentis used as a part of the liquid component, it is already solubilized andtherefore produces a much more homogeneous bone cement when it iscombined with the powder component. In addition, the amount of bindingagent needed is reduced in a liquid form, requiring less liquid to beused in the formulation, and resulting in a cement with strongermechanical strength.

It is also preferred that the binding agent of the present invention iswater soluble.

Examples of the binding agent which can be used in the invention,without limitation, are polyvinylpyrrolidone, a copolymer ofN-vinylpyrrolidone and vinylesters, a cellulose derivative, such ashydroxypropyl methyl cellulose, methyl cellulose, hydroxypropylcellulose, carboxymethyl cellulose, gelatin, xanthan gum, scleroglucan(ACTIGUM), sodium alginate and/or a mixture thereof.

Furthermore, the particle size and/or amount of the binding agent can beadjusted to modify the injectability (or viscosity) of the cementformulation.

In accordance with the present invention, the particle size of thebinding agent is between about 1 μm to about 2500 μm, preferably betweenabout 1 μm to about 1000 μm, and more preferably between 10 μm to about250 μm. This means that at least about 25%, preferably about 50%, morepreferably about 75% of the binding agent, by weight, falls within theseranges based on sieving.

With respect to the amount of the binding agent, the binding agent maybe present in an amount of between about 1% and about 15%, morepreferably between about 1% and about 3% based on the total weight ofthe formulation.

In a preferred embodiment of the present invention, the binding agent ofthe present invention is supplied to an end user as a liquid componentdissolved in a solvent. In such preferred embodiment, the binding agentmay be present in an amount of between about 3% and about 15%, morepreferably between about 7% and about 12% based on the total weight ofthe liquid component.

Calcium Phosphate Minerals

The at least one source of calcium phosphate useful in accordance withthe present invention generally includes numerous calcium phosphateminerals already known in the art, such as those taught by Brown andChow in U.S. Reissue Pat. 33,161 and 33,221, Chow and Takagi in U.S.Pat. Nos. 5,522,893, 5,542,973, 5,545,294, 5,525,148, 5,695,729 and6,375,992 and by Constantz in U.S. Pat. Nos. 4,880,610 and 5,047,031,teachings of which are incorporated herein by reference.

For example, the source of at least one calcium phosphate mineral inaccordance with the present invention includes tetra-calcium phosphate,di-calcium phosphate, tri-calcium phosphate, mono-calcium phosphate,β-tricalcium phosphate, α-tricalcium phosphate, oxyapatite, orhydroxyapatite and/or a mixture thereof.

In a preferred embodiment, two different calcium phosphate minerals areused in accordance with the present invention, more preferably one oftwo calcium phosphate minerals is tetra-calcium phosphate.

In another preferred embodiment, the at least one calcium phosphatemineral includes di-calcium phosphate and tetra-calcium phosphate, mostpreferably di-calcium phosphate dihydrate (also known as di-calciumphosphate dihydrous) (“DCPD”) and tetra-calcium phosphate (“TTCP”).

In yet another preferred embodiment, the at least one source of calciumphosphate mineral includes two calcium phosphate minerals, wherein oneof the two calcium phosphate minerals is stabilized using a stabilizingagent.

A stabilizing agent is any material (with at least one calcium phosphatemineral) that will allow the calcium phosphate mineral to set whenreacted after the calcium phosphate has been stored for a predeterminedperiod of time, preferably for at least 5 months, more preferably for atleast 3 months, and most preferably for at least 6 months or moreaccording to the accelerated aging test described in details below.

For example, the source of the calcium phosphate mineral which can beused with a stabilizing agent in accordance with the present inventionincludes tetra-calcium phosphate, di-calcium phosphate, tri-calciumphosphate, mono-calcium phosphate, β-tricalcium phosphate, α-tricalciumphosphate, oxyapatite, or hydroxyapatite and/or a mixture thereof.

In a preferred embodiment, the stabilizing is added during the processof making the calcium phosphate mineral to make the stabilized calciumphosphate mineral.

The preferred source for making the stabilized calcium phosphate isdi-calcium phosphate, more preferably DCPD.

Examples of the stabilizing agent which can be used in accordance withthe present invention, without any limitation, are MgO, MgO₂, Mg(OH)₂,MgHPO₄, MgHPO₄.3H₂O, MgHPO₄.7H₂O, Mg₃(PO₄)₂, Mg₃(PO₄)₂.4H₂O,Mg₃(PO₄)₂.8H₂O, Mg₃(PO₄)₂.22H₂O, MgCO₃, MgCO₃.3H₂O, MgCO₃.5H₂O,3MgCO₃Mg(OH)₂.3H₂O, MgCO₃Mg(OH)₂.3H₂O, Mg(C₃H₅O₃)₂.3H₂O, MgC₂O₄.2H₂O,Mg(C₄H₄O₆)₂.4H₂O, MgCO₃.CaCO₃, Mg₂P₂O₇, Mg (C₁₂H₂₃O₂)₂.2H₂O, Mg(C₁₄H₂₇O₂)₂, Mg (C₁₈H₃₃O₂)₂, or Mg (C₁₈H₃₅O₂)₂ and/or a mixture thereof.The most preferred stabilizing agent is magnesium oxide.

In another preferred embodiment, a stabilizing agent is provided in anamount from about 10 ppm to about 60 ppm, preferably from about 30 ppmto about 50 ppm, more preferably about 40 ppm relative to the totalweight of the calcium phosphate mineral to which the stabilizing agentis added to make the stabilized calcium phosphate mineral.

In a preferred embodiment when the at least one calcium phosphateincludes DCPD and TTCP, a stabilizing agent, such s magnesium oxide isprovided in an amount from about 10 ppm to about 60 ppm, preferably fromabout 30 ppm to about 50 ppm, more preferably about 40 ppm relative tothe total weight of the DCPD.

Furthermore, the particle size of the at least one calcium phosphate canbe adjusted to modify the rate of the rapid dissolution of calciumphosphate minerals during cement mixing and injection.

In accordance with the present invention, the particle size of the atleast one calcium phosphate is between about 0.4 μm to about 200 μm,preferably between about 5 μm to about 175 μm, and most preferablybetween 25 μm to about 70 μm, as measured by Becton Coulter's LS 13 3220series particle size analyzer as mentioned above, but using IsopropylAlcohol (IPA) as the carrier medium. This means that at least about 25%,preferably about 50%, and more preferably about 75% of the at least onecalcium phosphate, by weight, falls within these ranges based onsieving.

In a preferred embodiment wherein the at least one calcium phosphateincludes DCPD and TTCP, the particle size of the DCPD is between about0.4 μm to about 200 μm, preferably about 25 μm to about 70 μm, and mostpreferably about 40 μm to about 50 μm, and the particle size of TTCP isbetween about 0.4 μm to about 200 μm, preferably about 10 μm to about 30μm.

In another preferred embodiment of the present invention, the at leastone calcium phosphate of the present invention is supplied to an enduser as a powder component. In such preferred embodiment, the at leastone calcium phosphate may be present in an amount of between about 50%and about 90%, more preferably between about 60% and about 80% based onthe total weight of the powder component.

In yet another preferred embodiment, wherein the at least one calciumphosphate mineral includes two calcium phosphate minerals, morepreferably the stabilized DCPD and TTCP, the stabilized DCPD may bepresent in an amount of between about 15% and about 40%, more preferablybetween about 20% and about 30% based on the total weight of the powdercomponent, and TTCP may be present in an amount of between about 45% andabout 75%, more preferably between about 50% and about 70% based on thetotal weight of the powder component.

Sodium Phosphate Compound(s)

In accordance with the present invention, the at least one sodiumphosphate compound is used to speed the setting time of the bone cement.

Examples of sodium phosphates which can be used in the presentinvention, without limitation, are disodium hydrogen phosphateanhydrous, sodium dihydrogen phosphate monohydrate, sodium phosphatemonobasic monohydrate, sodium phosphate monobasic dihydrate, sodiumphosphate dibasic dihydrate, trisodium phosphate dodecahydrate, dibasicsodium phosphate heptahydrate, pentasodium tripolyphosphate, sodiummetaphosphate, and/or a mixture thereof.

In a preferred embodiment, the at least one sodium phosphate compound istwo sodium phosphate compounds, more preferably disodium hydrogenphosphate anhydrous and sodium dihydrogen phosphate monohydrate.

The particle size of the at least one sodium phosphate compound isbetween about 1 μm to about 2500 μm, preferably between about 1 μm toabout 1000 μm. This means that at least about 25%, preferably about 50%and more preferably about 75% of the sodium phosphate compound(s), byweight, falls within these ranges based on sieving.

In accordance with the present invention, the reaction retarding agentcan be provided as a powder component, or dissolved in a solvent andprovided as a liquid component.

The sodium phosphate compound may be present in an amount of betweenabout 0.5% and about 5%, more preferably between about 0.5% and about2.5%, based on the total weight of the total formulation.

In another preferred embodiment wherein the sodium phosphate compound issupplied to an end user as a liquid component, the sodium phosphatecompound may be present in an amount of between about 1% and about 20%,more preferably between about 1% and about 10%, based on the totalweight of the liquid component.

Solvent

Examples of solvent which can be used in accordance with the presentinvention includes, without limitation, water, blood, saline solution,PBS (phosphate buffered saline) and the like and the mixture thereof.The most preferred solvent is water.

The solvent may be present in an amount of between about 15% and about30%, more preferably between about 18% and about 25%, based on the totalweight of the total formulation.

In another preferred embodiment, the solvent may be present in an amountof between about 50% and about 95%, more preferably between about 75%and about 90%, based on the total weight of the liquid component.

Additive(s)

Various additives may be included in the inventive cements, slurries andpastes to adjust their properties and the properties of thehydroxyapatite products made from them. For example, proteins,osteoinductive and/or osteoconductive materials, X-ray opacifyingagents, medicaments, supporting or strengthening filler materials,crystal growth adjusters, viscosity modifiers, pore forming agents, andother additives and a mixture thereof may be incorporated withoutdeparting from the scope of this invention.

The inventive cement may be supplied to the user in a variety of forms,including as powders or as powder mixture which is later mixed with asolvent to make slurry or putty; or as a pre-mixed putty which maycontain a nonaqueous extender, e.g., glycerin and/or propylene glycol.

It may be supplied with or in the instrumentation which is used tointroduce the cement into the body, for example, a syringe, percutaneousdevice, cannula, biocompatible packet, dentula, reamer, file or otherforms which will be apparent to those of ordinary skill in the art.

It is contemplated that the cement in any of these forms, may be madeavailable to the surgeon, veterinarian or dentist via a kit containingone or more of its key components.

The cement is generally provided or employed in a sterilized condition.Sterilization may be accomplished, by e.g., radiation sterilization(such as gamma-ray radiation), moist heat sterilization, dry heatsterilization, chemical cold sterilization, and filtration.

Moreover, as will be recognized by those of skill in the art, numerousother specific techniques for preparation of each component (e.g. atleast one calcium phosphate mineral, preferably the stabilized calciumphosphate mineral, at least one reaction retarding agent, and at leastone binding agent and etc.) of the inventive cement may be employed.

For example, the conventional precipitation and crystallization methodscan be used in preparation of the calcium phosphate minerals. Drying ofthe precipitates and/or crystals can be accomplished using theconventional drying methods such as freeze drying, oven drying, vacuumdrying and the like.

Furthermore, each component described in accordance with the presentinvention herein (such as at least one reaction retarding agent, atleast one binding agent, solvents and additives and etc.) may also bepurchased if there is a commercially available product.

Similarly, the particle size reduction of these elements can beaccomplished by using, for example, a pestle and mortal, a ball mill, aroller mill, centrifugal-impact mill and sieve, cutter mill, attritionmill, chaser mill, fluid-energy mill and/or centrifugal-impactpulverizer.

This invention is illustrated by, but not limited to, the followingexamples. Although the following Examples may recite a certain order ofsteps of making the invention, the invention is not in anyway limited tothe order written.

EXAMPLE 1 Production of DCPD with 40 ppm of Magnesium

(1) 30% Phosphoric Acid Solution Preparation With 40 ppm MagnesiumAddition

To make the required 30% concentration of orthophosphoric acid (H₃PO₄),in a 5 ltr stainless beaker, 261 +/−2 mls of 85% orthophosphoric acidwas added to 737+/−2 mls of deionized water and the beaker was placed ontop of a hot plate set to 45° C. Then the temperature probe was placedin the beaker to measure the temperature of the acid solution and thehot plate was turned on to heat the solution to 45° C. The solution wasthen stirred at a speed of 200+/−10 rpm to ensure that the probe wasmeasuring a true representation of the beaker content. While the acidsolution was being heated to 45° C., 0.0413 grams of magnesium oxide(MgO) (equivalent to about 40 ppm magnesium content or about 0.006883%based on the weight of the DCPD) was added to the solution, which isherein also referred to as magnesium “spiked” solution or magnesium“spiked” orthophosphoric acid. Then the pH probes and temperature probeswere calibrated and put into the acid solution.

(2) Preparation of Calcium Carbonate Solution

0.45 kg of calcium carbonate (CaCO₃) was added into a 5 kg stainlesssteel beaker and 1 ltr of deionized water was added to the beaker. Thebeaker was then placed on top of a hot plate which was set to 40° C.Then the temperature probe was placed into the calcium carbonatesuspension and the hot plate was turned on. The calcium carbonatesuspension was then stirred at a speed of 575+/−50 rpm to ensure thatthe probe was measuring a true representation of the beaker content.

(3) Wet Chemical Precipitation

Once the magnesium spiked orthophosphoric acid reached the temperatureof 45° C. and calcium carbonate suspension reached the temperature of40° C., Watson-Marlow's Model 323u/D peristaltic pump system was set upto feed the carbonate suspension into the magnesium spikedorthophosphoric acid at a feed rate of 48+/−2 ml/min. The pH probe wasactivated in order to obtain the temperature/pH/time data at the start.Then the carbonate suspension was fed into the acid solution. Once thepH of the acid solution reached a pH of ˜3.6, the feed rate of thecarbonate suspension was stopped and the pH of the solution wasmonitored. The pH data from the beginning till the end of the carbonatefeed was recorded. Once the pH reached 4.75, the finaltemperature/pH/time data for the precipitate was recorded and all thetemperature and pH probes as well as the peristaltic tube from thesolution were removed. The reaction of magnesium, orthophosphoric acidand calcium carbonate produced the stabilized DCPD precipitate.

(4) Precipitate Rinsing

A Whatman #5 filter paper (2.5 μm pore size) was placed into eachBuckner funnel attached to a Buckner flask. Five (5) Buckner funnelsattached to Buckner flasks were needed per precipitation run. Then, theprecipitate solution (approximately 300 ml) was poured into each Bucknerfunnel attached to a Buckner flask and then a vacuum pump was turned on.The pump drew a vacuum and caused the water to be removed from theprecipitate while the filter paper kept the precipitate in the Bucknerfunnel. After a minimum of two minutes of suction, each Buckner funnelwas filled to the rim with deionized water (approx. 200-300 ml) in orderto rinse any excess reactants from the precipitate. The precipitate wasleft under the vacuum for a minimum time of 5 minutes in order to ensureremoval of any excessive free moisture.

(5) Freeze Drying

Next, a maximum of 300 grams (approximately half a precipitateproduction yield) was placed per freeze-drying tray in a manner ensuringthat the precipitate is spread out evenly on the tray. The filled trayswere then placed into Biopharma Process System's Model VirTis Genesis 25Super ES freeze dryer. Each tray contained a temperature probe in orderto monitor the precipitate temperature/moisture level during drying.Then the freeze dryer cycle was set to the program listed below and wasturned on.

TABLE 1 Freeze Drying Recipe for DCPD Temperature Time Vacuum Step (°C.) (minutes) (mTorr) *R −15 1 100 **H −15 120 100 R −5 120 200 H −5 240200 R 0 120 1000 H 0 600 1000 R 10 60 1000 H 10 30 1000 R 20 60 1000 H20 30 1000 *R = Ramp section of the freeze drying cycle. **H = Holdsection of the freeze drying cycle.

Once the precipitate has been dried using the freeze-drying cycle listedin Table 1, the precipitate required milling in order to reduce theaverage particle size so as to improve the final cement handling andsetting properties. This milling is performed using Glen Creston Ltd'sModel BM-6 roller ball-mill.

(6) Ball-Milling

3000+/−30 grams of alumina milling media (13.0 mm diameter×13.2 mmheight) was placed into each ball-mill jar. Then, 500+/−25 grams of thedried DCPD precipitates were added into each ball-mill jar and wereplaced on the ball-mill rollers. The ball-mill was set to 170 rpm and amill time of 30 minutes, and was turned on.

The ball-mill jar speed was monitored to ensure that it is rotating at85 rpm. Once the 30 minutes of milling has elapsed, the milling mediawas separated from the milled powder by sieving through the 8 mm screenprovided.

The milled and sieved powders were then placed into the freeze-dryingtrays and the freeze-drying procedure as detailed in the previoussection was repeated.

As will be recognized by those of skill in the art, other specifictechniques for preparation of the stabilized di-calcium phosphatecomponent of the inventive cement may be employed.

For example, one may also use the following freeze drying and ballmilling parameters in preparation of stabilized DCPD with 40 ppm ofmagnesium.

(7) Freeze Drying

A maximum of 500 grams was placed per freeze-drying tray in a mannerensuring that the precipitate is spread out evenly on the tray. Thefilled trays were then placed into Biopharma Process System's ModelVirTis Genesis 25 Super ES freeze dryer. Each tray contained atemperature probe in order to monitor the precipitatetemperature/moisture level during drying. Then the freeze dryer cyclewas set to one of the following preferred programs listed below and wasturned on.

TABLE 2 1^(st) Freeze Drying Parameters for DCPD Temperature Time VacuumStep (° C.) (minutes) (mTorr) *R −5 1 100 **H −5 480 100 R 0 120 1000 H0 600 1000 R 10 60 1000 H 10 90 1000 R 25 60 1000 H 25 90 1000 *R = Rampsection of the freeze drying cycle. **H = Hold section of the freezedrying cycle.

Once the precipitate has been dried using the freeze-drying cycle listedin Table 1, the precipitate required milling in order to reduce theaverage particle size so as to improve the final cement handling andsetting properties. This milling is performed using Glen Creston Ltd'sModel BM-6 roller ball-mill.

(8) Ball-Milling

3000+/−25 grams of alumina milling media (13.0 mm diameter×13.2 mmheight) was placed into each ball-mill jar. Then, 560+/−10 grams of thedried DCPD precipitates were added into each ball-mill jar and wereplaced on the ball-mill rollers. The ball-mill was set to 170 rpm and amill time of 25+/−2 minutes, and was turned on.

The ball-mill jar speed was monitored to ensure that it is rotating at87+/−5 rpm. Once the 25+/−2 minutes of milling has elapsed, the millingmedia was separated from the milled powder by sieving through the 8 mmscreen provided.

The particle size of the powder components (including DCPD and TTCP)were measured using the above mentioned Beckman Coulter's LS 13320Series particle size analyzer.

The milled and sieved powders (maximum weight of 375 g) were then placedinto the freeze-drying trays and the freeze-drying procedure as detailedin Table 3 below.

TABLE 3 2^(nd) Freeze Drying Parameters for DCPD Temperature Time VacuumStep (° C.) (minutes) (mTorr) *R −5 1 200 **H −5 60 200 R 0 60 1000 H 0120 1000 R 10 60 1000 H 10 30 1000 R 20 60 1000 H 20 60 1000 R 30 601000 H 30 300 1000 *R = Ramp section of the freeze drying cycle. **H =Hold section of the freeze drying cycle.

EXAMPLE 2 Production of DCPD with 60 ppm of Magnesium

(1) 30% Phosphoric Acid Solution Preparation with 60 ppm MagnesiumAddition

To make the required 30% concentration of orthophosphoric acid (H₃PO₄),in a 5 ltr stainless beaker, 261 +/−2 mls of 85% orthophosphoric acidwas added to 737+/−2 mls of deionized water and the beaker was placed ontop of a hot plate set to 47° C. Then the temperature probe was placedin the beaker to measure the temperature of the acid solution and thehot plate was turned on to heat the solution to 47° C. The solution wasthen stirred at a speed of 200+/−10 rpm to ensure that the probe wasmeasuring a true representation of the beaker content. While the acidsolution was being heated to 47° C., 0.0620 grams of magnesium oxide(MgO) (equivalent to about 60 ppm magnesium content or about 0.0085%based on the weight of the DCPD) was added to the solution. Then the pHprobes and temperature probes were calibrated and put in to the acidsolution.

(2) Preparation of Calcium Carbonate Solution

0.45 kg of calcium carbonate (CaCO₃) was added into a 5 kg stainlesssteel beaker and 1 ltr of deionized water was added to the beaker. Thebeaker was then placed on top of a hot plate which was set to 42° C.Then the temperature probe was placed into the calcium carbonatesuspension and the hot plate was turned on. The calcium carbonatesuspension was then stirred at a speed of 575+/−50 rpm to ensure thatthe probe was measuring a true representation of the beaker content.

(3) Wet Chemical Precipitation

Once the magnesium spiked orthophosphoric acid reached the temperatureof 47° C. and calcium carbonate suspension reached the temperature of42° C., Watson-Marlow's Model 323u/D peristaltic system was set up tofeed the carbonate suspension into the magnesium spiked orthophosphoricacid at a feed rate of 48+/−2 ml/min. Then the pH probe was activated inorder to obtain the temperature/pH/time data at the start. Then thecarbonate suspension was fed into the acid solution. Once the pH of theacid solution reached a pH of ˜3.6, the feed rate of the carbonate wasstopped and the pH of the solution was monitored. The pH data from thebeginning till the end of the carbonate feed was recorded. Once the pHreached 5.00, the final temperature/pH/time data for the precipitate wastaken and all the temperature and pH probes as well as the peristaltictube from the solution were removed. The reaction of magnesium,orthophosphoric acid and calcium carbonate produced the stabilized DCPDprecipitate.

(4) Precipitate Rinsing

A Whatman #5 filter paper (2.5 μm pore size) was placed into eachBuckner funnel attached to a Buckner flask. Five (5) Buckner funnelsattached to Buckner flasks were needed per precipitation run. Then, theprecipitate solution (approximately 300 ml) was poured into each Bucknerfunnel attached to a Buckner flask and then a vacuum pump was turned on.The pump drew a vacuum and caused the water to be removed from theprecipitate while the filter paper kept the precipitate in the Bucknerfunnel. After a minimum of two minutes of suction, each Buckner funnelwas filled to the rim with deionized water (approx. 200-300 ml) in orderto rinse any excess reactants from the precipitate. The precipitate wasleft under the vacuum for a minimum time of 5 minutes in order to ensureremoval of any excessive free moisture.

(5) Freeze Drying

A maximum of 300 grams (approximately half a precipitate productionyield) was placed per freeze-drying tray in a manner ensuring that theprecipitate is spread out evenly on the tray. The filled trays were thenplaced into Biopharma Process System's Model VirTis Genesis 25 Super ESfreeze dryer. Each tray contained a temperature probe in order tomonitor the precipitate temperature/moisture level during drying. Thenthe freeze dryer cycle was set to the program listed below and wasturned on.

TABLE 4 Freeze Drying Parameters for DCPD Temperature Time Vacuum Step(° C.) (minutes) (mTorr) *R −15 1 100 **H −15 120 100 R −5 120 200 H −5240 200 R 0 120 1000 H 0 600 1000 R 10 60 1000 H 10 30 1000 R 20 60 1000H 20 30 1000 *R = Ramp section of the freeze drying cycle **H = Holdsection of the freeze drying cycle

Once the precipitate has been dried using the freeze-drying cycle listedin Table 4, the precipitate required milling in order to reduce theaverage particle size so as to improve the final cement handling andsetting properties. This milling is performed using Glen Creston's ModelBM-6 roller ball-mill.

(6) Ball-Milling

3000+/−30 grams of alumina milling media (13.0 mm diameter×13.2 mmheight) was placed into each ball-mill jar. Then, 500+/−25 grams of thedried DCPD precipitates were added into each ball-mill jar and wereplaced on the ball-mill rollers. The ball-mill was set to 180 rpm and amill time of 32 minutes, and was turned on.

The ball-mill jar speed was monitored to ensure that it is rotating at95 rpm. Once the 32 minutes of milling has elapsed, the milling mediawas separated from the milled powder by sieving through the 8 mm screenprovided. The milled and sieved powders have a particle size withingenerally a range of about 0.4 to about 200 μm, preferably about 35+/−20μm, as measured by Beckman Coulter's Model LS 13320 Series particle sizeanalyzer as explained above. The milled and sieved powders were thenplaced into the freeze-drying trays and the freeze-drying procedure asdetailed in the previous section was repeated.

As will be recognized by those of skill in the art, other specifictechniques for preparation of the stabilized di-calcium phosphatecomponent of the inventive cement may be employed.

For example, one may also use the following freeze drying and ballmilling parameters in preparation of stabilized DCPD with 60 ppm ofmagnesium.

(7) Freeze Drying

A maximum of 500 grams was placed per freeze-drying tray in a mannerensuring that the precipitate is spread out evenly on the tray. Thefilled trays were then placed into Biopharma Process System's ModelVirTis Genesis 25 Super ES freeze dryer. Each tray contained atemperature probe in order to monitor the precipitatetemperature/moisture level during drying. Then the freeze dryer cyclewas set to the program listed below and was turned on.

TABLE 5 1^(st) Freeze Drying Parameters for DCPD Temperature Time VacuumStep (° C.) (minutes) (mTorr) *R −5 1 100 **H −5 480 100 R 0 120 1000 H0 600 1000 R 10 60 1000 H 10 90 1000 R 25 60 1000 H 25 90 1000 *R = Rampsection of the freeze drying cycle. **H = Hold section of the freezedrying cycle.

Once the precipitate has been dried using the freeze-drying cycle listedin Table 5, the precipitate required milling in order to reduce theaverage particle size so as to improve the final cement handling andsetting properties. This milling is performed using Glen Creston's ModelBM-6 roller ball-mill.

(8) Ball-Milling

3000+/−25 grams of alumina milling media (13.0 mm diameter×13.2 mmheight) was placed into each ball-mill jar. Then, 560+/−10 grams of thedried DCPD precipitates were added into each ball-mill jar and wereplaced on the ball-mill rollers. The ball-mill was set to 180 rpm and amill time of 25+/−2 ppm, and was turned on.

The ball-mill jar speed was monitored to ensure that it is rotating at87+/−5 rpm. Once the 25+/−2 minutes of milling has elapsed, the millingmedia was separated from the milled powder by sieving through the 8 mmscreen provided. The milled and sieved powders have a particle sizewithin generally a range of about 0.4 to about 200 μm, preferably about47+/−22.5 μm, as measured by Beckman Coulter's Model LS 13320 Seriesparticle size analyzer as explained above. The milled and sieved powders(maximum weight of 375 g) were then placed into the freeze-drying traysand the freeze-drying procedure as detailed in Table 6 below.

TABLE 6 2^(nd) Freeze Drying Parameters for DCPD Temperature Time VacuumStep (° C.) (minutes) (mTorr) *R −5 1 200 **H −5 60 200 R 0 60 1000 H 0120 1000 R 10 60 1000 H 10 30 1000 R 20 60 1000 H 20 60 1000 R 30 601000 H 30 300 1000 *R = Ramp section of the freeze drying cycle. **H =Hold section of the freeze drying cycle.

EXAMPLE 3 Production of Tetra Calcium Phosphate (TTCP)

(1) TTCP Cake Preparation

To form the preferred TTCP, the TTCP slurry mixture needs to comprise a50% w/w solution of solid to liquid with the solid component comprising60.15% di-calcium phosphate anhydrous (DCPA) and 39.85% CaCO₃ and theliquid component comprising purified water. To prepare a batch of TTCP“cakes” for sintering in the furnace, i.e., 3500 grams of TTCP cakes,2105.25+/−0.5 grams of DCPA was accurately weighed out into a clean 5liter Buckner flask. To this, 1394.75+/−0.5 grams of CaCO₃ were added.To this powder mixture, 3.5 liters of deionized water was added. Table 7shows the specific amounts and percentages of these components.

TABLE 7 Raw Material Weights for the Production of TTCP Cakes MaterialWeight (g) Ratio (%) CaCO₃ 1394.75 ± 1 39.85 DCPA 2105.25 ± 1 60.15Water  3500.00 ± 10 100

The Buckner flask was then sealed with appropriate rubber bung andnozzle attachments. The Buckner flask was placed in Glen Creston Ltd'sModel T10-B turbular mixer for 20 minutes for homogenous mixing. Table 8shows the turbular blending parameters.

TABLE 8 Turbular Parameters for Blending of TTCP Raw Materials ParameterSetting Speed (rpm) 44 ± 4 Time (mins) 20 Buckner Flask Volume (%) 80

While the Buckner flask was mixing, the appropriate vacuum tubing to afour-point manifold was connected: one end was attached to the vacuumpump, the other four points were attached to the nozzle attachments onfour Buckner flasks. A 9 cm diameter polypropylene Buckner funnel wasassembled onto each of the four Buckner flasks, respectively, andWhatman grade 5 filter paper was placed into each Buckner funnel. Theblended DCPA/CaCO₃/water mixture was removed from the turbular mixer,and the rubber bung was removed. Then, each polypropylene Buckner funnelwas completely filled with the TTCP slurry. The TTCP slurry was vacuumdried using the vacuum pump, and the vacuum was drawn for a minimum of 5minutes until the cakes formed solid top surfaces. Further vacuum dryingcould be used if required to form solid cakes. Once the cakes wereformed, the vacuum on the Buckner flasks was released. Each funnel wasremoved from the flask and the inverted funnel was gently tapped toremove the cake. Each funnel produced a cake of approximately 300 grams.

Then the spent filter paper was removed, the funnel was washed out withpurified water and a fresh filter paper was placed in the funnel. Theabove steps were repeated until all the slurry solution is in a cakeform. The TTCP slurry was hand mixed every four to five cakepreparations to ensure homogeneity. If upon removal from the funnel, thecake was broken or has a rough surface, the deionized water was sprayedonto the surface to bind loose fragments together. Any loose remainingfragments were reintroduced to the slurry mixture to form new cakes.

(2) Sintering

All cakes were stacked onto a stainless steel tray and dried for twohours at 200° C. in Lenton's Model AWF 12/42 muffle furnace to drive offexcess moisture prior to sintering. The TTCP cakes were now ready to besintered using the sintering program detailed in Table 9.

TABLE 9 Sintering Parameters for Firing of TTCP Cakes Temperature TimeRamp Rate Step (° C.) (minutes) (° C./min) Ramp 800 100  8 Dwell 800≧120 n/a Ramp 1550 94  8 Dwell 1550 720 n/a Cool 800 ≦10 75 Cool 20 1552

The sintered cakes were transferred to a vacuum Buckner flask before thetemperature dropped below 150° C. unless the material was to be crushedand milled immediately.

(3) Jaw Crushing

TTCP was processed through Glen Creston's jaw crusher to reduce thegranules to a manageable size, preferably in the range of about 2.5 toabout 7.5 mm prior to processing through the co-mill. The sintered TTCPcakes were manually broken using a mortar and pestle to particle sizesof approximately one inch in diameter before loading into the jawcrusher. In this instance, the jaw crusher gap was set to 5 mm.

(4) Co-Milling Of TTCP Granules

TTCP was processed through Quadro Inc.'s co-mill (Model Quadro Comil197) to reduce the material to the final particle size. The mill speedwas set to 5000+/−300 rpm. The impeller gap was set to 0.375″ usingstainless steel washers. To co-mill the TTCP powder, the jaw-crushedTTCP powders were slowly fed into the co-mill at a rate of approximately700 grams/min, ensuring that the co-mill did not become clogged withexcess powder. (See Table 10 for co-milling parameters.)

TABLE 10 Parameters for Co-Milling the Jaw-Crushed Sintered TTCP CakesParameter Setting Screen No. 0.024″ Impeller speed 5000 rpm

(5) Ball-Milling

Glen Creston Ltd's Model BM-6 roller ball mill was used to ball-mill thesintered, jaw crushed and co-milled TTCP. The ball milling parametersfor the dry milling of the sintered, jaw crushed and co-milled TTCP arelisted in Table 6. For the dry milling of the TTCP, a total of 3000+/−25grams of alumina milling media (13.0 mm diameter×13.2 mm height) wasweighed into an alumina ball-milling jar, to which 600+/−25 grams of theTTCP was added. The ball mill parameters are outlined in Table 11 below.

TABLE 11 Milling Parameters for the Dry Ball-Milling of TTCP TTCP BallMill Parameters Speed (rpm) 87 +/− 5 Time (mins) 360 +/− 15 Media fillweight 3000 +/− 25  (grams) TTCP weight (grams) 600 +/− 25

The milled and sieved powders have a particle size within generally arange about 0.4 to about 200 μm, preferably about 10 to 30 μm. Theparticle size was measured as explained above using Beckton Coulter's LS13 320 series particle size analyzer.

EXAMPLE 4 Preparation of a Reaction Retarding Agent (e.g. TrisodiumCitrate)

Trisodium citrate (which was procured from ADM, Co. located in Cork,Ireland) was processed through Quadro Inc.'s co-mill (Model Quadro Comil197) to reduce the material to the final particle size. The mill speedwas set to 300+/−50 rpm. The screen size used was 0.039″. The impellergap was set to 0.05″ using stainless steel washers. The trisodiumcitrate powder was slowly fed into the co-mill at a rate ofapproximately 700 grams/min, ensuring that the co-mill did not becomeclogged with excess powder.

EXAMPLE 5 Production of the Powder Component Containing DCPD, TTCP andTrisodium Citrate

28.6 weight % of stabilized DCPD with 60 ppm of magnesium, 61 weight %of tetra-calcium phosphate and 10.4 weight % of tri-sodium citrate weremixed to form a mixture.

TABLE 12 Powder Component of Bone Cement % Weight/total weight ofChemical Mw Powder Chemical Name Formula (grams) Component StabilizedDCPD with CaHPO₄•2H₂O 172.05 28.6 40 ppm of Magnesium Tetra-CalciumCa₄O(PO₄)₂ 366.26 61 Phosphate Tri-Sodium Citrate Na₃C₆H₅O₇•2H₂O 294.1110.4 TOTAL 100

EXAMPLE 6 Production of Liquid Component Comprising Sodium Phosphatesand Polyvinylpyrrolidone (PVP)

Into one liter of high purity water, 29.8 grams of disodium hydrogenphosphate anhydrous, 85.6 grams of sodium dihydrogen phosphatemonohydrate and 90.0 grams of PVP were added and stirred until they werecompletely dissolved. All of the above-mentioned materials are readilyavailable commercial products, and in this particular case, wereprocured following manufacturers.

The details of this preferred water-based solution are outlined in Table13 below.

TABLE 13 Liquid Component of Bone Cement % weight/total Chemical Mwweight Chemical Name Formula (grams) (weight (g)) DiSodium HydrogenNa₂HPO₄ 141.96 2.5 Phosphate Anhydrous Sodium Dihydrogen NaH₂PO₄•H₂O137.99 7.1 Phosphate Monohydrate Polyvinylpyrrolidone [—C₆H₉NO—]_(n)(111.1)_(n) 7.5 Water H₂O 18 82.9

Below is another preferred embodiment of the liquid component of thepresent invention using sodium carboxymethylcellose as a binding agent.

TABLE 14 Liquid Component of Bone Cement Percentage Chemical Mw %Chemical Name Formula (grams) w/w Di-Sodium Hydrogen Na₂HPO₄ 141.96 2.7Dibasic Anhydrous Sodium Phosphate NaH₂PO₄•H₂O 137.99 7.7 MonobasicHydrate Sodium [—Na₂C₁₆H₂₂O₁₄—]_(n) (484.14)_(n) 2.2carboxymethlycellulose Water H₂O 18 87.4

EXAMPLE 8 Mixing of the Powder Component with the Liquid Component toProduce the Final Cement

For the final cement usage, stabilized DCPD was mixed with the TTCP inan equimolar ratio (i.e. DCPD-to-TTCP ratio of 31.97:68.03). Thentrisodium citrate was added to the mixture of DCPD and TTCP to produce afinal ratio of DCPD:TTCP:sodium citrate of 28.6:61:10.4. This powdermixture was blended to ensure the formation of a mixture.

Then the liquid component was added to the powder mixture using aliquid-to-powder ratio of 0.32 to form a settable final product.

The bone cements of the present invention were subjected to an array ofqualification tests to verify that they meet the performancerequirements. The bone cements of the present invention were analyzed,for example, for their (1) long-term stability, (2) wet fieldpenetration resistance, (3) compression strength, (4) mixing evaluation,(5) injectability, (6) percent washout, (7) hardware pull out, (8)hydroxyapatite conversion, and (9) shrinkage, which are described inmore details below.

EXAMPLE 9 Test for Long-Term Stability

The DCPD powders produced as described in Examples 1 and 2 were analyzedfor long-term stability using an X-ray diffractometer. First, as shownin FIGS. 1 and 3, the X-ray powder diffraction patterns of the initialdry DCPD powders of Example 1 and Example 2 were collected usingRigaku's X-ray diffractometer.

Then, 5 grams of DCPD powders were packaged in a topaz bowl andheat-sealed with a breathable Tyvek lid. This bowl was then placed in afoil pouch with 10 grams of silicon desiccant. The foil pouch is thenheat-sealed. The sealed foil pouch was then placed in a climatic ovenset at 50° C. and aged for a set period of time. It has been determinedthat storage under these conditions for 52 days is equivalent to 1 yearreal time aging.

The stabilized DCPD powders were stored in a climatic oven set at 50° C.for 77 days, and the DCPD powders of Example 2 were stored in a climaticoven set at 50° C. for 91 days for accelerated aging tests.

After the exposure in the accelerated aging test conditions, the X-raypowder diffraction patterns of the DCPD powders of Example 1 and Example2 were collected again using the same Rigaku's X-ray diffractometer. Asshown in FIGS. 2 and 4, said stabilized DCPD containing magnesiumexhibited characteristic x-ray diffraction peaks of DCPD. Morespecifically, after the exposure in the accelerated aging testconditions as mentioned above, the X-ray powder diffraction patterns ofthe DCPD powders of Example 1 and Example 2, said stabilized DCPDpowders exhibited x-ray diffraction peaks at 11.605, 20,787, 23.391,26.5, 29.16, 30.484, 31.249, 31.936, 33.538, 34.062, 35.45, 36.34 and39.67+/−0.2 degrees two-theta after an accelerated aging test of 52 daysat 50° C. in a sealed container.

Similarly, a powder component of the final formulation (for example, apowder component comprising stabilized DCPD, TTCP or a powder componentcomprising stabilized DCPD, TTCP and a reaction retarding agent such astrisodium citrate) is also tested for long-term stability in the samefashion described above.

After the exposure in the accelerated aging test conditions for apredetermined period of time, the powder component can be tested for itsstability by mixing it with a solvent to see whether it sets to form acement. Alternatively, the powder component can be tested for stabilityusing an x-ray diffractometer to determine whether the x-ray diffractionpattern exhibits the characteristic x-ray diffraction peaks of theoriginal calcium phosphates of the powder component (such as DCPD andTTCP).

Based upon the Arrehnius equation as defined in ASTM F 1980, thefollowing accelerated aging times equate to real time room temperatureshelf-life:

Accelerated Time Accelerated Time Real Time at 40° C. at 50° C. 1.5months ~13 days ~6.5 days 3 month ~26 days ~13 days 6 months 53 days 26days 1 year 105 days 52 days 2 years 210 days 105 days

EXAMPLE 10 Wet Field Penetration Resistance Test

The bone cements produced as described in Example 8 was also tested forwet field penetration resistance. The test consists of applying a loadapplicator through the cement at specific time points. The loadapplicator was made up of a small cylindrical stainless steel needlewith 1/16″ in diameter. Two minutes and thirty seconds after initialblending of the powder and liquid constituents, the cement was depositedinto a long groove (¼″ wide×¼″ deep) of a block heated at 32° C. Threeminutes after the initial blending, the cement was subjected to aconstant flow of saturated phosphate solution using a Watson Marlow 323peristaltic pump set at 20 rpm. The solution was kept constant at 32° C.Four minutes after the initial blending, the load applicator was made topenetrate the cement for 1.5 mm and the result force was recorded. Thetest is repeated every minute for 13 minutes. A stress/displacementcurve was obtained at the end of the test to show the increase inresistance of the cement over time. The preferred penetration resistancerequirements for the present invention were greater than 3500 psi (24.1MPa) after 10 minutes from being mixed. Although the results below weremeasured after 10 minutes from the initial blending, the same test canbe performed to determine whether the cement has set at 8 minutes or 9minutes from the initial blending. Table 15 shows the results of thepenetration resistance tests using the bone cements produced accordingto Example 8.

TABLE 15 Penetration Resistance Test Results Bone Cement Containing DCPDwith 40 ppm Of Magnesium (Example 1) Sample Number Results 1 4416 psi(30.45 MPa) @ 10 min 2 4587 psi (31.63 MPa) @ 10 min 3 4559 psi (31.44MPa) @ 10 min 4 4649 psi (32.06 MPa) @ 10 min 5 4155 psi (28.65 MPa) @10 min 6 4549 psi (31.37 MPa) @ 10 min Sample Average 4486 psi (30.93MPa) @ 10 min

EXAMPLE 11 Mixing Evaluation

Five random non experienced users of bone cements were presented withthe powder and liquid components of the bone cement formulation of thepresent invention. The users were asked to mix and transfer a cementinto the syringe fitted with a 10 gauge cannula at the ambienttemperature of between 18° C. to 22° C. when they felt the mix wasready. The times taken for mixing and then transferring were measuredfrom the initial blending of the powder and liquid components asrecorded in the table below.

TABLE 16 End of User Mixing time Transfer time User 1 35 secs 1 min 24secs User 2 54 secs 1 min 53 secs User 3 53 secs 2 mins 5 secs User 4 42secs 1 min 55 secs User 5 45 secs 1 min 52 secs

The filled syringes were then taken to a test machine to carry out theinjectability and wet field penetration tests, which are described indetails below.

EXAMPLE 12 Injectability Test

As explained above in Example 11, the powder and liquid components weremixed to produce a cement paste and the paste was transferred to asyringe fitted with a 10 gauge cannula. Then, a downward force wasapplied on the plunger using a mechanical test machine with the speedset at 25 mm/min. A downward force was applied after 3 minutes and 30seconds from initial blending of the powder and liquid components of thecement formulation. The readings were taken from the force/displacementcurve at 25 mm displacement which is equivalent to 4 minutes and 30seconds. For this test, maximum force at that time point is not toexceed 200N, preferably 150N. The results are recorded in the tablebelow.

TABLE 17 Injection force at Test sample 3 mins 30 sec (N) 1 73.1 2 73.33 77.3 4 111.6 5 67.2 Average 80.5

EXAMPLE 13 Wash Out Test

This test was performed in vivo during an animal study. Canine cranialdefect was used as the site for evaluation of the washout. 5 cc ofcement was implanted in the canine defect with the defect temperature of32° C. and at 8 minutes, the cement was subjected to a pulse lavage froman Interpulse® squirt gun. The wash out was deemed to be acceptable asno significant amount of the cement was lost.

EXAMPLE 14 Hardware Pull Out Test

The cement was mixed and injected into an artificial cancellous bonematerial. Three minutes after the initial blending of the powder andliquid components, the artificial cancellous bone with injected bonecement (composite) was immersed into a phosphate solution, which was at32° C. The composite was removed from the solution to be drilled inpreparation for the screw at 9 minutes. At 10 minutes, the hardware (4.5mm cortical screw) was screwed into the drilled composite and placed inthe test rig ready for testing. At 12 minutes, the screw was pulled outof the composite using a mechanical test machine. The screw pull outforce is to exceed 100N. The results are recorded in the table below.

TABLE 18 Test sample Pull out strength (N) 1 156.2 2 193.4 3 530 4 554 5500 Average 386.72

EXAMPLE 15 Hydroxyapatite Conversion

The cement was mixed and allowed to age for the appropriate time pointin a phosphate solution at 37° C. At the specified time point, thecement was removed from the solution and dried in an oven at 70° C. Thecement was then pulverized with the aid of a mortar and pestle andplaced in a Rigaku x-ray diffractometer for XRD analysis. The sample wasscanned between 10 and 40 degrees 2 theta and the results recorded on agraph of 2 theta versus intensity. The peaks for the sample werecompared to JCPDS pattern 9-432 (for Hydroxyapatite) and the peakintensities at 2 theta of 29.23, 29.81, 31.77 and 32.20 were recordedfor the calculation of HA conversion. The peaks at 2 theta of 29.23 and29.81 correspond to TTCP and the peaks at 31.77 and 32.20 correspond toHA. The HA conversion was then calculated and the result at 2 weeks mustbe greater than 60% HA conversion. The results are recorded in the tablebelow.

TABLE 19 Test sample HA conversion % (2 wks) 1 61.3 2 76.7 3 62.7Average 66.9

EXAMPLE 16 Shrinkage

The powder and liquid components were mixed and the paste was injectedinto a mold (21.3 mm×6.1 mm). A total of three samples were prepared.The samples were allowed to set prior to removal from the mold. Thevolume was calculated from the diameter and height of each specimen. Thesamples were then incubated at 37° C. in a phosphate solution for 24hours. They were subsequently removed and dried. Using a calibratedvernier, the specimens were measured again and the change in volumechange calculated using the new measurements.

TABLE 20 Test sample Volume change % 1 0.63 2 0.94 3 0.54 Average 0.70

As these and other variations and combinations of the features discussedabove can be utilized without departing from the present invention asdefined by the claims, the foregoing description of the preferredembodiments should be taken by way of illustration rather than by way oflimitation of the invention as defined by the claims. It is therefore tobe understood that numerous modifications may be made to theillustrative embodiments and that other arrangements may be devisedwithout departing from the spirit and scope of the present invention asdefined by the appended claims.

1. A calcium phosphate composition comprising: (1) at least two calciumphosphate minerals, (2) at least one reaction retarding agent, (3) atleast one binding agent, (4) at least one sodium phosphate, wherein oneof said at least two calcium phosphate minerals contains a stabilizingagent.
 2. The calcium phosphate composition of claim 1, wherein saidcomposition is rapid setting.
 3. The calcium phosphate composition ofclaim 1, wherein said composition is injectable.
 4. The calciumphosphate composition of claim 1, wherein said at least two calciumphosphate minerals are di-calcium phosphate and tetra-calcium phosphate.5. The calcium phosphate composition of claim 4, wherein said di-calciumphosphate is di-calcium phosphate dihydrate.
 6. The calcium phosphatecomposition of claim 1, wherein said one of said at least two calciumphosphate minerals containing said stabilizing agent is di-calciumphosphate dihydrate.
 7. The calcium phosphate composition of claim 6,wherein said stabilizing agent is magnesium.
 8. The calcium phosphatecomposition of claim 6, wherein said stabilizing agent is provided in anamount from about 10 ppm to about 60 ppm relative to the total weight ofsaid dicalcium phosphate dihydrate.
 9. The calcium phosphate compositionof claim 1, wherein said composition has a long term shelf-life.
 10. Thecalcium phosphate composition of claim 1, wherein said at least twocalcium phosphate minerals have a particle size of between about 0.4 μmand about 200 μm.
 11. The calcium phosphate composition of claim 4,wherein said di-calcium phosphate has a particle size of between about25 μm and about 70 μm.
 12. The calcium phosphate composition of claim 4,wherein said tetra-calcium phosphate has a particle size of betweenabout 10 μm and about 30 μm.
 13. The calcium phosphate composition ofclaim 1, wherein said at least two calcium phosphate minerals areprovided in an amount of between about 50% and about 90% based on thetotal weight of said composition.
 14. The calcium phosphate compositionof claim 1, wherein said reaction retarding agent is citric acid,trisodium citrate, tripotassium citrate, sodium pyrophosphate, ethylenediamine tetra acetic acid sodium salt or a mixture thereof.
 15. Thecalcium phosphate of claim 14, wherein said reaction retarding agent istrisodium citrate.
 16. The calcium phosphate of claim 14, wherein saidreaction retarding agent has a particle size of between about 1 μm andabout 1000 μm.
 17. The calcium phosphate of claim 16, wherein saidreaction retarding agent has a particle size of between about 170 μm toabout 220 μm.
 18. The calcium phosphate of claim 14, wherein saidreaction retarding agent is provided in an amount of between about 3%and about 20% based on the total weight of said composition.
 19. Thecalcium phosphate of claim 14, wherein said reaction retarding agent isprovided in an amount of between about 5% and about 10% based on thetotal weight of said composition.
 20. The calcium phosphate of claim 1,wherein said binding agent is polyvinylpyrolidone, a copolymer ofN-vinylpyrrolidone and vinyl esters, a cellulose derivative, gelatin,xanthan gum, scleroglucan (actigum), sodium alginate or a mixturethereof.
 21. The calcium phosphate composition of claim 20, wherein saidbinding agent is a cellulose derivative.
 22. The calcium phosphatecomposition of claim 20, wherein said binding agent ispolyvinylpyrrolidone.
 23. The calcium phosphate of claim 20, whereinsaid binding agent has a particle size of between about 1 μm and about2500 μm.
 24. The calcium phosphate of claim 20, wherein said bindingagent is provided in an amount of between about 1% and about 15% basedon the total weight of said composition.
 25. The calcium phosphate ofclaim 20, wherein said binding agent is provided in an amount of betweenabout 1% and about 3% based on the total weight of said composition. 26.The calcium phosphate composition of claim 1, wherein said at least onesodium phosphate compound is di-sodium hydrogen phosphate anhydrous,sodium dihydrogen phosphate monohydrate, sodium phosphate monobasicmonohydrate, sodium phosphate monobasic dihydrate, sodium phosphatedibasic dihydrate, trisodium phosphate dodecahydrate, or dibasic sodiumphosphate heptahydrate, pentasodium tripolyphosphate, sodiummetaphosphate, or a mixture thereof.
 27. The calcium phosphatecomposition of claim 1, wherein said at least one sodium phosphatecompound includes two sodium phosphate compounds.
 28. The calciumphosphate composition of claim 27, wherein said two sodium phosphatecompounds are sodium hydrogen phosphate anhydrous and sodium dihydrogenphosphate monohydrate.
 29. The calcium phosphate of claim 26, whereinsaid at least one sodium phosphate compound has a particle size ofbetween about 1 μm and about 2500 μm.
 30. The calcium phosphate of claim26, wherein said at least one sodium phosphate compound is provided inan amount of between about 0.5% and about 5% based on the total weightof said composition.
 31. The calcium phosphate composition of claim 1,further comprising a solvent.
 32. The calcium phosphate composition ofclaim 31, wherein said solvent is water, blood, phosphate bufferedsaline, a saline solution or a mixture thereof.
 33. The calciumphosphate composition of claim 31, wherein said solvent is provided inan amount of between about 50% and about 95%.
 34. The calcium phosphatecomposition of claim 1, further comprising an additive.
 35. The calciumphosphate composition of claim 34, wherein said additive is protein,osteoinductive material, osteoconductive material, x-ray opacifyingagent, medicament, supporting filler material, strengthening fillermaterial, crystal growth adjuster, viscosity modifier, pore formingagent, or a mixture thereof.
 36. A calcium phosphate composition that isprepared by a process including the steps of: (a) providing at least twocalcium phosphate minerals, at least one reaction retarding agent, atleast one binding agent, and at least one sodium phosphate compound, and(b) mixing said at least two calcium phosphate minerals, said at leastone reaction retarding agent, said at least one binding agent, and saidat least one sodium phosphate compound in a solvent, wherein one of saidat least two calcium phosphate minerals is a stabilized calciumphosphate mineral containing a stabilizing agent.
 37. The calciumphosphate composition of claim 36, wherein said stabilizing agent isadded during a process of making said stabilized calcium phosphatemineral.
 38. The calcium phosphate composition of claim 36, wherein saidstabilizing agent is provided in an amount from about 10 ppm to about 60ppm relative to the weight of said stabilized calcium phosphate mineral.39. The calcium phosphate composition of claim 37, wherein saidstabilizing agent is MgO, MgO₂, Mg(OH)₂, MgHPO₄, MgHPO₄.3H₂O,MgHPO₄.7H₂O, Mg₃(PO₄)₂, Mg₃(PO₄)₂.4H₂O, Mg₃(PO₄)₂.8H₂O, Mg₃(PO₄)₂.22H₂O,MgCO₃, MgCO₃.3H₂O, MgCO₃.5H₂O, 3MgCO₃Mg(OH)₂.3H₂O, MgCO₃Mg(OH)₂.3H₂O,Mg(C₃H₅O₃)₂.3H₂O, MgC₂O₄.2H₂O, Mg(C₄H₄O₆)₂·4H₂O, MgCO₃·CaCO₃, Mg₂P₂O₇,Mg(C₁₂H₂₃O₂)₂.2H₂O, Mg(C₁₄H₂₇O₂)₂, Mg(C₁₈H₃₃O₂)₂, or Mg(C₁₈H₃₅O₂)₂ or amixture thereof.
 40. A calcium phosphate composition comprising: (a) apowder component comprising
 1. at least one calcium phosphate mineral,and
 2. a reaction retarding agent, and (b) a liquid componentcomprising
 1. at least one binding agent,
 2. at least one sodiumphosphate compound, and
 3. a solvent.
 41. A kit for forming a calciumphosphate bone cement comprising: (a) a first container comprising apowder mixture of stabilized di-calcium phosphate dihydrate containingfrom about 10 ppm to about 60 ppm of magnesium, a second calciumphosphate mineral, and at least one reaction retarding agent, and (b) asecond container comprising a solvent comprising at least one bindingagent, and at least one sodium phosphate compound.
 42. The kit of claim41 further comprising a delivery device for application of a mixture ofsaid powder mixture and said solvent.
 43. A method for making a calciumphosphate bone cement comprising: (a) preparing a powder componentcontaining at least one calcium phosphate mineral, and a reactionretarding agent, and (b) preparing a liquid component by dissolving atleast one binding agent and at least one sodium phosphate compound in asolvent, and (c) mixing said powder component with said liquidcomponent.
 44. A calcium phosphate composition comprising: (a) at leastone calcium phosphate mineral, (b) at least one binding agent, (c) atleast one sodium phosphate, and (d) trisodium citrate.
 45. A calciumphosphate composition comprising: (a) at least one calcium phosphatemineral, (b) at least one reaction retarding agent, (c) at least onesodium phosphate, and (d) polyvinyl pyrrolidone.
 46. A calcium phosphatecomposition comprising: (a) at least one calcium phosphate mineral, (b)at least one binding agent, (c) at least one reaction retarding agent,and (d) at least two sodium phosphate compounds.
 47. A calcium phosphatecomposition comprising: (a) at least one calcium phosphate mineral, (b)at least one binding agent, (c) at least one sodium phosphate, and (d)at least one reaction retarding agent having a particle size betweenabout 1-1000 μm.
 48. A calcium phosphate composition comprising: (a) atleast one calcium phosphate mineral, (b) at least one reaction retardingagent, (c) at least one binding agent, and (d) at least one sodiumphosphate having a particle size between about 1-2500 μm.